The blood is the means for delivering oxygen and nutrients and removing waste products from the tissues. The blood is composed of plasma in which red blood cells (RBCs or erythrocytes), white blood cells (WBCs), and platelets are suspended. Red blood cells comprise approximately 99% of the cells in blood, and their principal function is the transport of oxygen to the tissues and the removal of carbon dioxide therefrom.
The left ventricle of the heart pumps the blood through the arteries and the smaller arterioles of the circulatory system. The blood then enters the capillaries, where the majority of the delivery of oxygen, exchange of nutrients and extraction of cellular waste products occurs. (See, e.g., A. C. Guyton, “Human Physiology And Mechanisms Of Disease” (3rd. ed.; W. B. Saunders Co., Philadelphia. Pa.), pp. 228-229 (1982)). Thereafter, the blood travels through the venules and veins in its return to the right atrium of the heart. Though the blood that returns to the heart is oxygen-poor compared to that which is pumped from the heart, when at rest, the returning blood still contains about 75% of the original oxygen content.
The reversible oxygenation function (i.e., the delivery of oxygen) of RBCs is carried out by the protein hemoglobin. In mammals, hemoglobin has a molecular weight (MW) of approximately 64,000 Daltons and is composed of about 6% heme and 94% globin. In its native form, it contains two pairs of subunits (i.e., it is a tetramer), each containing a heme group and a globin polypeptide chain. In aqueous solution, hemoglobin is present in equilibrium between the tetrameric (MW 64,000 Daltons) and dimeric (MW 32,000 Daltons) forms. Outside of the RBC, the dimers are prematurely excreted by the kidney (plasma half-life of approximately 2-4 hours). Along with hemoglobin, RBCs contain stroma (the RBC membrane), which comprises proteins, cholesterol, and phospholipids.
Due to the demand for blood products in hospitals and other settings, extensive research has been directed at the development of blood substitutes. A “blood substitute” is a blood product that is capable of carrying and supplying oxygen to the tissues. Hemoglobin-based oxygen carriers (HBOCs) are blood substitutes containing hemoglobins. HBOCs have a number of uses, including replacing blood lost during surgical procedures and following acute hemorrhage, and for resuscitation procedures following traumatic injury. Essentially, HBOCs can be used for any purpose in which banked blood is currently administered to patients. (See, e.g., U.S. Pat. Nos. 4,001,401 to Bonson et al., and 4,061,736 to Morris et al.)
The development of HBOCs is especially important, given the fact that the current human blood supply is limited. For this reason, human blood is normally only used in circumstances when it is medically necessary. This usually means that human blood is not appropriate for prophylactic use, such as “blood doping” (i.e. administering whole blood for the purpose of enhancing performance by increasing the oxygen carrying capacity of the blood). Accordingly, neither the use of whole blood nor HBOCs for prophylactic indications are widespread, and in most cases are considered to be a somewhat questionable practice.
The administration of HBOCs to patients prior to surgery has been previously suggested in combination with the removal of autologous blood from the patients (i.e. acute normovolemic hemodilution or “ANH”) which could be returned later in the procedure, if needed, or after surgery. See, for example, PCT WO 98/37909. Such patients are considered herein not to be “normovolemic” at the time of surgery. However, this procedure does not address the need for prophylactic measures to avoid the detrimental primary effects of surgical procedures such as hemodynamic stability, and only addresses the secondary effects of blood loss associated with surgery.
Enhancing hemodynamic stability during surgery requiring general anesthesia is important for two fundamental reasons. First, hemodynamic instability caused by blood loss or other factors can lead to tissue damage and even death. For example, hemorrhagic hypotension and anaphylactic shock are conditions which result from significant blood loss leading to reduced tissue oxygenation. For patients with such medical conditions, it is desirable and often critical for their survival to stabilize their blood pressure and to increase the amount of oxygen provided to body tissues by their circulatory systems.
Second and most importantly, hemodynamic instability, even minor and transient, may affect a patient's post-surgical recovery. This instability may occur anywhere throughout the body, and is often manifested as a “hypotensive event,” which is usually recorded as a decrease in blood pressure. Such events can occur as a result of fluctuations of localized hemodynamic properties during general anesthesia, even when there is no loss of blood. These events can cause cognitive damage and other complications that exacerbate recovery following surgery. For example, elderly patients undergoing invasive surgical procedures such as hip replacements would benefit from any prophylactic treatment that would enhance their hemodynamic stability during surgery. In addition, such patients are often not suitable candidates for ANH, and enhancing their hemodynamic stability would be expected to lessen their need for transfusions using donor blood.
The use of plasma expanders and volume replacements to maintain hemodynamic stability is widespread. However, these non-oxygen carrying solutions only dilute the oxygen capacity of the blood, even without concomitant ANH, and may actually cause hemodynamic instability in some instances. In addition to plasma expanders and volume replacements, crystalloid solutions have also been suggested for use in maintaining hemodynamic stability. However, the administration of these solutions may result in excessive water retention and edema, which can also cause fluctuations in hemodynamic properties.
Accordingly, there is a need for methods to enhance hemodynamic stability which may result in transient hypotensive events that do not diminish the blood's inherent oxygen carrying capacity. In accordance with this goal, the present invention relates to a method of enhancing hemodynamic stability by administering compositions comprising hemoglobin-based oxygen carriers such as specially formulated polyalkylene oxide modified hemoglobins.